Liposomes are artificial vesicles composed of concentric lipid bilayers separated by water-compartments and have been extensively investigated as drug delivery vehicles. Due to their structure, chemical composition and colloidal size, all of which can be well controlled by preparation methods, liposomes exhibit several properties which may be useful in various applications. The most important properties are colloidal size, i.e. rather uniform particle size distributions in the range of 20 nm to 10 μm, and special membrane and surface characteristics. Liposomes are used as carriers for drugs and antigens because they can serve several different purposes. Liposome encapsulated drugs are inaccessible to metabolizing enzymes. Conversely, body components (such as erythrocytes or tissues at the injection site) are not directly exposed to the full dose of the drug. The duration of drug action can be prolonged by liposomes because of a slower release of the drug in the body. Liposomes have a direction potential, which means that targeting options change the distribution of the drug in the body. Cells use endocytosis or phagocytosis mechanism to take up liposomes into the cytosol. Furthermore, liposomes can protect a drug against degradation (e.g. metabolic degradation). However, liposomes may confront a defect that drugs (such as anti-cancer drugs) encapsulated in liposomes cannot be well released.
Photodynamic therapy (“PDT”) is a process whereby light of a specific wavelength is directed to tissues undergoing treatment or investigation that have been rendered photosensitive through the administration of a photoreactive or photosensitizing agent. Initiation of photodynamic activity is caused by excitation of the photodynamic compound by light that falls within its absorption band. The wavelength specificity depends on the molecular structure of the photodynamic compound; a greater degree of conjugation within a molecule leads to greater absorbance at longer wavelengths. Activation of photodynamic compounds occurs with subablative light fluences. Toxicity is achieved by O2 radical toxicity. The singlet O2 reacts with, for example, double bonds to produce reactive species, for example, organoperoxides. These, in turn, initiate free radical chain reactions which degrade and disorganize membranes, uncouple oxidative phosphorylation, and lead to cellular disruption. However, PDT is only suitable for superficial therapy.
Photodynamic therapy (PDT) is being used experimentally to treat a wide variety of malignant tumors and certain other diseases, such as psoriasis and papillomatosis. This technology is disclosed in U.S. Pat. Nos. 4,649,151, 4,866,168, 4,889,129 and 4,932,934, the disclosure of which is incorporated herein by reference. Photodynamic therapy has proven to be very effective in destroying abnormal tissue such as cancer cells. In this therapy, a photoreactive agent having a characteristic light absorption wavelength or waveband is first administered to the patient. Abnormal tissue in the body is known to selectively absorb certain photoreactive agents to a much greater extent than normal tissue, e.g., tumors of the pancreas and colon may absorb two to three times the volume of these agents, compared to normal tissue. Certain porphyrins and related tetrapyrrolic compounds tend to localize in abnormal tissue, including malignant tumors and other hyperproliferative tissue, such as hyperproliferative blood vessels, in much higher concentrations than in normal tissues, so they are useful as a tool for the treatment of various type of cancers and other hyperproliferative tissue by photodynamic therapy (PDT). However, most of the porphyrin-based photosensitizers including PHOTOFRIN™ (a purified hematoporphyrin derivative (HpD) approved worldwide for the treatment of tumors) clear slowly from normal tissue, so patients must avoid exposure to sunlight for a significant time after treatment.
U.S. Pat. Nos. 5,705,518 and 5,770,619 of Richer et al. describe a PDT experiment where a photosensitizer, benzoporphyrin derivative mono-acid ring A (BPD-MA) was prepared as its liposome and intravenously administered to a mouse having transplanted M-1 tumor, followed by irradiating the mouse with an exciting laser beam. Based on these experiments, a method is proposed for destroying or impairing an area of neovascularization, which comprises transcutaneously irradiating said area with a laser light before an administered photosensitizer has permeated into dermal tissue or other normal tissues, so that the dermal phototoxicity can be avoided. In U.S. Pat. Nos. 5,705,518 and 5,770,619, Richter et al. refer to mono-L-aspartyl chlorin e6 as one example of the photosensitizer, and indicate that the method as proposed could be used to destroyed or impair an area of neovascularization formed in the eye.
U.S. Pat. No. 5,277,913 provides a triggered release liposomal delivery system that selectively releases its contents in response to illumination or reduction in pH. The liposomes contain an amphipathic lipid, such as a phospholipid, having two chains derived from fatty acid that allow the lipid to pack into a bilayer structure. One or both of the alkyl chains contain a vinyl ether functionality that is cleaved by reactive oxygen species (ROS) or acid. A photosensitizer is incorporated into the liposomal cavity or membrane, and produces ROS or acid when illuminated to cleave the vinyl ether functionality and disrupt the liposomal membrane to release the vesicle contents.
The use of PDT for the treatment of various types of disease has been limited due to the inherent features of photosensitizers (PS). These include high cost, extended retention in the host organism, substantial skin photo toxicity, low solubility in physiological solutions (which also reduces its usefulness for intravascular administration as it can provoke thromboembolic accidents), and low targeting effectiveness. These disadvantages, particularly of PS in the prior art, has led to the administration of very high doses of a photosensitizer, which dramatically increase the possibility of accumulation of the photosensitizer in non-damaged tissues and the accompanying risk of affecting non-damaged sites.
Since the application of photodynamic therapy in the treatment of cancer and other diseases is increasing rapidly, there is also a greater demand for a new PDT regimen.